Heart failure (HF) is a progressive disorder characterized by left ventricular (LV) enlargement and a fall in ejection fraction that results in low cardiac output, and increased mortality and morbidity. Acutely, switching the substrate of the heart away from fatty acids toward carbohydrate oxidation has been shown to markedly improve global LV performance in both patients with HF as well as in dogs with experimentally-induced chronic HF. The effects of chronic modulation of fatty acid oxidation in HF on LV function and chamber remodeling are poorly understood, thus creating a major knowledge gap in our understanding of how chronic partial inhibition of the fatty acid oxidation pathway influences myocardial performance and remodeling of the failing heart. The goals of this project are to elucidate the role of fatty acid metabolism in the progression of HF, and to determine whether chronic partial inhibition of myocardial fatty acid oxidation in HF influences LV function and LV chamber remodeling both globally and at the cellular level. All studies will be conducted using the well established canine coronary microembolization model of chronic HF. Myocardial substrate oxidation will be manipulated by partial inhibition of myocardial fatty acid oxidation at the level of transport of long-chain fatty acyl groups into the mitochondria, by direct inhibition of the fatty acid oxidation enzyme 3-ketoacylthiolase, and by beta-adrenergic receptor blockade. In addition, we will assess the effects of stimulation of myocardial fatty acid oxidation by feeding a high fat diet on the progression of HF. Cardiac substrate oxidation and LV remodeling will be measured over the course of evolving HF. Molecular remodeling will be evaluated based on measurements of fetal gene expression. Our hypothesis is that partial inhibition of myocardial fatty acid oxidation will result in attenuation or reversal of cellular and molecular remodeling, while elevated fatty acid oxidation due to high fat feeding will accelerate the cellular and molecular remodeling processes.